Understanding Primary and Secondary Hyperparathyroidism
Primary Hyperparathyroidism (PHPT)
Primary hyperparathyroidism is characterized by autonomous parathyroid gland overproduction of PTH, resulting in hypercalcemia with elevated or inappropriately normal PTH levels. 1
Pathophysiology and Causes
- Single parathyroid adenoma accounts for approximately 80% of primary hyperparathyroidism cases, making it the most common etiology 1
- Multigland disease (hyperplasia) affects 15-20% of patients with primary hyperparathyroidism 1
- Parathyroid carcinoma is rare, occurring in less than 1% of cases 1
- The hallmark is autonomous PTH secretion that is independent of calcium levels, leading to dysregulated calcium homeostasis 2
Biochemical Profile
- The combination of hypercalcemia with elevated or inappropriately normal PTH levels is diagnostic of primary hyperparathyroidism 2, 1
- Serum phosphate is typically low or low-normal 2
- Most patients demonstrate hypercalciuria (>250-300 mg/day) due to increased filtered calcium load from hypercalcemia 2, 1
- The American College of Endocrinology recommends measuring serum calcium (corrected for albumin) and intact PTH simultaneously to establish the diagnosis 2
Clinical Presentation
- Symptomatic primary hyperparathyroidism with target organ involvement (kidney stones, bone disease, neuromuscular symptoms) is more common in countries without routine biochemical screening 1
- Many patients are now diagnosed incidentally through routine laboratory testing before symptoms develop 3
Secondary Hyperparathyroidism (SHPT)
Secondary hyperparathyroidism is characterized by elevated PTH in response to chronic hypocalcemia, hyperphosphatemia, or vitamin D deficiency, with normal or low serum calcium levels. 4, 5
Pathophysiology and Causes
- SHPT represents a compensatory physiologic response where increased PTH production attempts to correct calcium homeostasis but fails due to underlying organ dysfunction or reduced calcium availability 4
- The three primary drivers are: hyperphosphatemia, hypocalcemia, and vitamin D deficiency 5
- Chronic kidney disease is the most common cause, as declining renal function leads to phosphate retention, decreased calcitriol production, and impaired calcium absorption 4, 5, 6
- Other causes include malabsorption syndromes, vitamin D deficiency rickets, hepatobiliary disease, and chronic intestinal malabsorption 7
Biochemical Profile in CKD-Related SHPT
- Normal or low serum calcium with elevated PTH is the hallmark finding 2, 5
- Hyperphosphatemia is defined as serum phosphorus >4.6 mg/dL in CKD stages 3-4, or >5.5 mg/dL in stage 5 5
- Hypocalcemia is defined as corrected serum calcium <8.4 mg/dL 5
- Vitamin D deficiency is defined as 25(OH)D <30 ng/mL 5
- Alkaline phosphatase is often elevated, suggesting high bone turnover 5
Monitoring Recommendations by CKD Stage
- For CKD Stage 3 (GFR 30-59 mL/min/1.73 m²): measure calcium, phosphorus, and PTH annually 5
- For CKD Stage 4 (GFR 15-29 mL/min/1.73 m²): measure calcium and phosphorus every 3-6 months 5
- For CKD Stage 5 (GFR <15 mL/min/1.73 m² or on dialysis): measure calcium and phosphorus monthly initially, then every 1-3 months once stable 5
- The National Kidney Foundation recommends targeting PTH range of 150-300 pg/mL (not normal range) for CKD Stage 5 5
Critical Management Principle
- Never target "normal" PTH levels (<65 pg/mL) in dialysis patients, as this causes adynamic bone disease with increased fracture risk and loss of bone buffering capacity for calcium 5
Tertiary Hyperparathyroidism (THPT)
Tertiary hyperparathyroidism is marked by hypercalcemia with elevated PTH, representing autonomous PTH hypersecretion after longstanding secondary hyperparathyroidism. 1, 8
Key Distinguishing Features
- The parathyroid glands become autonomously hypersecreting after prolonged stimulation, losing their normal feedback regulation 4, 8
- Most commonly encountered following kidney transplantation in patients with long-standing chronic kidney disease 4, 1
- Unlike secondary hyperparathyroidism, PTH remains elevated despite rising serum calcium levels, manifesting as hypercalcemic hyperparathyroidism 4
- Typically involves multigland disease (parathyroid hyperplasia) 1
Key Diagnostic Distinctions
Primary vs Secondary Hyperparathyroidism
| Feature | Primary HPT | Secondary HPT |
|---|---|---|
| Calcium | Elevated | Normal or low |
| PTH | Elevated or inappropriately normal | Elevated |
| Pathophysiology | Autonomous PTH secretion | Compensatory PTH response |
| Common Cause | Parathyroid adenoma (80%) | Chronic kidney disease |
Important Diagnostic Pitfalls
- Vitamin D deficiency can complicate interpretation of PTH levels in both conditions and must be assessed 2, 3
- Vitamin D deficiency can suppress urine calcium excretion in primary hyperparathyroidism patients, potentially masking hypercalciuria 2
- Different PTH assay generations measure different PTH fragments and can yield significantly different values, requiring use of assay-specific reference ranges 4, 2
- The diagnosis of normocalcemic primary hyperparathyroidism should only be made after careful exclusion of all causes of secondary hyperparathyroidism 3